Experiments were run to determine the effect of oral gavage treatment with the cyclopentane influenza virus neuraminidase inhibitor peramivir (BCX-1812, RWJ-270201) in influenza A (H1N1) virus-infected mice that had their immune system suppressed by cyclophosphamide (CP) therapy or in severe combined immune deficient (SCID) mice. Treatment of CP-immunosuppressed mice with peramivir using doses of 100, 10, or 1 mg/kg/day was begun 2.5 or 8 days post-virus exposure and continued twice daily for 3 or 5 days. The 5-day therapy was more effective than the 3-day treatment, as seen by significantly increased survivor numbers, lessened decline in arterial oxygen saturation, reduced lung consolidation, and inhibition of lung virus titers. Infected SCID mice were also responsive to peramivir therapy begun 8 days after virus exposure and continued for 5 days, although antiviral effects did not include prevention of death and were dependent upon the viral challenge dose received. These data indicate that peramivir may have potential for treatment of influenza virus-infected immunosuppressed patients.